However, a follow-up study suggested that in the same cannabis-smoking patients, but not in the non-users, volume reductions in gray matter and white matter (in medial and lateral temporal regions, thalamus, basal ganglia, prefrontal cortex) were associated with the observed widespread cognitive deficitsReference 701. A number of studies, both in patients suffering from MS and in animal models of the disease, suggest the disorder is associated with changes in endocannabinoid levels, although the findings are conflictingReference 667Reference 668Reference 672-Reference 675. Lastly, a four-week, prospective, double-blind, randomized, cross-over clinical study of 5 mg daily doses of dronabinol in 24 adult women with severe, chronic anorexia nervosa reported a small, yet significant increase in body mass index (BMI) compared to placeboReference 322. One study in a mouse model of anorexia nervosa reported conflicting resultsReference 665, while another study in a rat model reported a significant attenuation in weight loss only at high doses of Δ9-THC (2.0 mg/kg/day Δ9-THC i.p.)Reference 666. The most commonly prescribed dose of dronabinol in this study was 2.5 mg/m2 oral solution every 6 h (as needed), and the median number of dronabinol doses received per hospitalization was 3.5.
This may be explained in part by the notion that for certain patients a degree of sedation and euphoria may be perceived as beneficial during chemotherapy. In addition to THC, CBD, THCA and CBDA, two other phytocannabinoids THCV and cannabidivarin (CBDV) have been studied, though to a far lesser extent, for their potential to alleviate nausea in animal modelsReference 620. THCV at a dose of 10 mg/kg (i.p.) and CBDV at a dose of 200 mg/kg (i.p.) have been shown to reduce acute nausea in rats, potentially through a CB1 receptor-independent mechanism, but nothing is known about their ability to suppress anticipatory nauseaReference 626. A subsequent study examined the effects of combining CBD and THC, and CBDA and THC on acute nausea and vomitingReference 117.
In contrast, a cross-sectional survey examining the benefits associated with cannabis use in patients with fibromyalgia reported a statistically significant benefit in the mental health component summary score of the SF-36 QoL questionnaire in patients who used cannabis compared to non-usersReference 184. However, no significant differences between cannabis and non-cannabis users were found in the other SF-36 domains, in the Fibromyalgia Impact Questionnaire, or the Pittsburgh Sleep Quality Index.
THCA at doses of 0.5 and 0.05 mg/kg (i.p.) reduced behaviours modelling acute nausea and vomiting, and at a dose of 0.05 mg/kg (i.p.) reduced behaviours modelling anticipatory nausea in animal models of acute and anticipatory nausea, and vomitingReference 623. A significant proportion ( %) of patients undergoing chemotherapy experience anticipatory nausea during treatment and once it develops, it is refractory to standard treatment with 5-HT3 antagonistsReference 620. Non-specific anti-anxiety treatments (e.g. benzodiazepines) are used to treat anticipatory nausea but drawbacks include significant sedationReference 620.
Evidence from clinical studies with Epidiolex® (oral CBD) suggests efficacy and tolerability of Epidiolex® for drug-resistant seizures in treatment-resistant Dravet syndrome or Lennox-Gastaut syndrome. The available evidence from pre-clinical and limited clinical studies suggests certain cannabinoids (CBD) may have anti-epileptiform and anti-convulsive properties, whereas CB1R agonists (THC) may have either pro- or anti-epileptic properties. Prolonged use of ingested or inhaled cannabis was associated with poorer performance on various cognitive domains (information processing speed, working memory, executive function, and visuospatial perception) in patients with MS according to one cross-sectional studyReference 233.
Sixty percent of the pediatric patients in this study were reported to have had a "good" response to dronabinol. Limitations of this study include retrospective design, lack of a comparison group, lack of chemotherapy standardization, and lack of standardized anti-emetic regimens. While prescription cannabinoids present clear advantages over placebo in the control of CINV, the evidence from randomized clinical trials shows cannabinoids to be clinically only slightly better than conventional dopamine D2-receptor antagonist anti-emeticsReference 210Reference 637. In some cases, patients appeared to prefer the cannabinoids to these conventional therapies despite the increased incidence of adverse effects such as drowsiness, dizziness, dysphoria, depression, hallucinations, paranoia, and arterial hypotension.
Higher doses of either THC (1.0 and 10 mg/kg i.p.) and/or CBDA (1.0 and 10 µg/kg i.p.) were effective in reducing anticipatory nausea. The higher dose of THC (10 mg/kg) was associated with hypoactivity, and this was not attenuated by CBDA. Additional work has revealed novel and important roles for cannabinoid acids (i.e. THCA, CBDA) in suppressing nausea and vomiting in animal modelsReference 116Reference 117Reference 622Reference 623Reference 625. In one study, when administered alone, a very low dose (0.5 µg/kg i.p.) of CBDA suppressed behaviour modelling acute nausea, and a subthreshold dose of CBDA (0.1 µg/kg i hemp seed oil.p.), when administered along with ondansetron at a dose of 1 µg/kg produced an enhancement of the acute anti-nausea effectReference 625. In addition, the effective dose of CBDA that attenuated acute nausea was approximately times lower than the effective dose for CBDReference 625.
Endocannabinoids such as anandamide and 2-AG have been shown to have analgesic or anti-nociceptive effects at peripheral, spinal, and central levels, mainly by virtue of their ability to stimulate the activity of the cannabinoid receptors, although other receptors (i.e. TRPV1) are also likely involvedReference 779. Peripheral inhibition of FAAH and MAGL enzymes (which hydrolyze anandamide and 2-AG respectively) and the resulting increase in the respective synaptic levels of anandamide and 2-AG has been shown to reduce nociception in animal models of acute and chronic painReference 762Reference 767Reference 780-Reference 791. Therefore, the upregulation of COX-2 expression in chronic pain states may promote the additional production of these pro-nociceptive metabolites both peripherally and centrally thus contributing to nociception and painReference 765. Although in vitro studies show that THCV binds with relatively high affinity at CB1 receptorsReference 112Reference 748, THCV does not appear to be a potent CB1 receptor agonistReference 112Reference 263Reference 748. Instead, experimental studies suggest THCV acts more like a CB1 receptor antagonist and a potent CB2 receptor partial agonistReference 18Reference 112Reference 263Reference 748Reference 749.
The study showed that 2.5 mg/kg CBD (i.p.), when combined with 1 mg/kg THC (i.p.), resulted in significant suppression of acute nausea and vomiting in an animal model and similarly, when 0.05 mg/kg (i.p.) CBDA was combined with 1 mg/kg THC, acute nausea and vomiting were significantly suppressed. Singular administration of either 2.5 mg/kg CBD, 1 mg/kg THC, or 0.05 mg/kg (i.p.) CBDA was not associated with any suppression of acute nausea and vomiting. Additional animal studies have shown that administration of subthreshold doses of THC (0.01 and 0.1 mg/kg i.p.) and CBDA (0.01 and 0.1 µg/kg i.p.) reduced acute nausea, and higher doses of THC (1.0 and 10 mg/kg i.p.) or CBDA (1.0 and 10 µg/kg i.p.) alone also reduced acute nauseaReference 116. In contrast to the effect seen for acute nausea, combined subthreshold doses of THC and CBDA did not suppress anticipatory nausea in animalsReference 116.
At higher doses however, THCV appears to have some agonist activity at the CB1 receptorReference 18. Furthermore, in vitro studies suggest THCV has some anti-epileptiform effects at micromolar concentrationsReference 112 and in vivo studies suggest THCV (0.25 mg/kg) has some limited anti-convulsant effects in one mouse model of epilepsyReference 112Reference 266.